Core Research for Evolutional Science and Technology (CREST) Laboratory, Medical Innovation Center and Center for Innovation in Immunoregulation Technology and Therapeutics, Kyoto University Graduate School of Medicine

Core Research for Evolutional Science and Technology (CREST) Laboratory, Medical Innovation Center and Center for Innovation in Immunoregulation Technology and Therapeutics, Kyoto University Graduate School of Medicine

Abstract

Inflammation in the colon contributes significantly to colorectal cancer development. While aspirin reduces the colorectal cancer risk, its action mechanism, especially in inflammation in tumor microenvironment, still remains obscure. Here we examined this issue by subjecting mice deficient in each prostaglandin (PG) receptor to colitis-associated cancer model. Deficiency of PGE receptor subtype EP2 selectively reduced, and deficiency of EP1 and EP3 enhanced, the tumor formation. EP2 is expressed in infiltrating neutrophils and tumor-associated fibroblasts in stroma, where it regulates expression of inflammation- and growth-related genes in a self-amplification manner. Notably, expression of cytokines such as TNF-α and IL-6, a chemokine, CXCL1, a PG-producing enzyme, COX-2 and Wnt5A was significantly elevated in tumor lesions of wild type mice but this elevation was significantly suppressed in EP2-deficient mice. Intriguingly, EP2 stimulation in cultured neutrophils amplified expression of TNF-α, IL-6, CXCL1, COX-2 and other pro-inflammatory genes synergistically with TNF-α and EP2 stimulation in cultured fibroblasts induced expression of EP2 itself, COX-2, IL-6 and Wnt genes. EP2 expression in infiltrating neutrophils and tumor-associated fibroblasts was also found in clinical specimen of ulcerative colitis-associated colorectal cancer. Bone marrow transfer experiments suggest that EP2 in both cell populations is critical for tumorigenesis. Finally, administration of a selective EP2 antagonist potently suppressed tumorigenesis in this model. Our study has thus revealed that EP2 in neutrophils and tumor-associated fibroblasts promotes colon tumorigenesis by amplifying inflammation and shaping tumor microenvironment, and suggests that EP2 antagonists are promising candidates of aspirin-alternative for chemoprevention of colorectal cancer.